The objective of this research is to understand the neurobiological basis for sex differences in alcoholism using an animal model designed to investigate the development of habitual responding with relevance for compulsive alcohol-seeking and taking behavioral patterns. Our proposed studies will investigate the interaction between corticostriatal circuits involved in habitual (i.e., stimulus-response) and goal-directed (i.e., response-outcome) behavior. These studies will focus on the role for corticostriatal alterations in dopamine neurotransmission that likely contribute to an intricate balance between goal-directed and habitual patterns of behavior. Previous studies suggest that women progress through the landmark stages from initial use to dependence at a faster rate than men, and the proposed series of experiments will investigate whether the faster rate of habit formation that we have observed in female rodents extends to habitual responding for alcohol. Such findings of genetic sex differences in habit formation for a natural reinforcer suggest inherent differences in corticostriatal circuitry that could underlie differences in habit formation for alcohol. Additionally, we have shown that dopamine infusions into the ventromedial prefrontal cortex can restore goal-directed responding in rats trained to express an instrumental, food-reinforced, habit. Together these studies form the basis for our hypothesis that female rats will progress toward habitual patterns of alcohol-seeking and taking more rapidly than male rats and that the development of habitual responding for alcohol will depend upon increased dopamine transmission in the dorsolateral, but not dorsomedial, striatum, and on decreased dopamine transmission in the ventromedial, but not dorsomedial, prefrontal cortex. Aim I will determine whether there is a sex difference in the rate of habit formation in rats when alcohol serves as the reinforcer. Subsequent experiments will address the neurobiological mechanisms (e.g., gonadal hormones and/or sex chromosome genes) for this potential sex difference. Aim II will use parallel procedures to examine whether dopamine transmission in the medial prefrontal cortex or dorsal striatum contributes to the performance of an alcohol habit. Subsequent experiments will address which dopamine receptors contribute to regionally specific behavioral effects. We believe that this focus provides an innovative approach because no previous research has examined sex differences in habit formation for a drug reinforcer or the role of corticostriatal dopamine neurotransmission in the goal-oriented and stimulus-bound components of alcohol responding. These data will provide the foundation for the complete analysis of genetic and hormonal contributions to sex differences in habitual responding for alcohol and cues associated with alcohol. Further, the data obtained will provide the first direct comparison of prefrontal cortical and dorsal striatal dopamine involvement in habitual responding. PUBLIC HEALTH RELEVANCE Alcoholism is characterized by the development of habitual drinking patterns that occur regardless of the societal or health consequences. Previous work has indicated that habits for alcohol consumption develop faster than for natural reinforcers, and that females may have a genetic predisposition to develop habits faster. The aim of this research is to determine if females develop alcohol habits more rapidly than males, and to determine how corticostriatal neurocircuitry regulates alcohol habit formation. The results of this research will help determine therapeutic targets to help alcoholics maintain abstinence by inhibiting the ability of strong habits to control behavior, and will determine if earlier interventions for female alcoholics can improve recovery. [unreadable] [unreadable] [unreadable]